A synthesis of sulfonamide analogs of platensimycin employing a palladium-mediated carbonylation strategy

Article abstract of DOI:10.1016/j.tetlet.2009.04.105

The monodentate ligand 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane (PA-Ph) is shown to be highly effective in palladium-catalyzed carbonylative cross-coupling. Aryl and vinyl halides were efficiently converted to carboxylic acids, amides and to primary, secondary, and tertiary esters, respectively. Application of the Pd(OAc)₂/PA-Ph (1:1) catalyst system proved critical in the methoxycarbonylation of a functionalized nitroresorcinol halide, allowing convenient access to novel platensimycin sulfonamide analogs.

Full text of DOI:10.1016/j.tetlet.2009.04.105

Tetrahedron Letters 50 (2009) 4087–4091
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A synthesis of sulfonamide analogs of platensimycin employing
a palladium-mediated carbonylation strategy
*
James McNulty , Jerald J. Nair, Alfredo Capretta
Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1
a r t i c l e i n f o
a b s t r a c t
Article history:
The monodentate ligand 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane (PA-Ph) is
shown to be highly effective in palladium-catalyzed carbonylative cross-coupling. Aryl and vinyl halides
were efficiently converted to carboxylic acids, amides and to primary, secondary, and tertiary esters,
respectively. Application of the Pd(OAc)2/PA-Ph (1:1) catalyst system proved critical in the methoxycarb-
onylation of a functionalized nitroresorcinol halide, allowing convenient access to novel platensimycin
sulfonamide analogs.
Received 6 April 2009
Revised 23 April 2009
Accepted 24 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Organopalladium cross-coupling reactions are among the most
selective and reliable methods for carbon–carbon bond formation.1
Palladium-catalyzed carbonylation is a useful, atom-economical
method for the selective introduction of the carbonyl group,2 mak-
ing carboxylic acids, esters, and amides readily accessible from
aryl, vinyl, and aliphatic halides (or halide equivalents) and olefins.
These reactions, originally established in the mid-70s by the pio-
neering work of Heck and co-workers,3 have found a number of
synthetic applications4 and have been utilized industrially.5 Our
group has been involved in the development of hindered tertiary
phosphines and active catalytic systems for palladium-catalyzed
cross-coupling reactions,6,7 including the use of 1,3,5,7-tetra-
and a direct application toward the synthesis of the platensimycin
aromatic core.
CH3
Ph
O
P
P
H3C
P
P
CH3
O
O
CH3
phosphorinane 2
dtbpx 3
PA-Ph 1
methyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane
(PA-Ph)
1,6a–e phosphorinanes6f such as 2 and more recently the bidentate
bis(di-tert-butylphosphino)-o-xylene (dtbpx) 3.6g Bulky, electron-
rich phosphines benefit both oxidative addition and reductive
elimination steps in cross-coupling reactions.8 A catalytic system
incorporating Pd2(dba)3ÁCHCl3 and PA-Ph was shown to promote
Suzuki cross-coupling of aryl iodides, bromides, and chlorides with
a variety of aryl boronic acids under mild conditions in solution6a
and on a solid-phase platform.6b In addition, efficient amination,
Sonogashira and ketone arylation reactions of aryl halides were
demonstrated,6c,d while a Pd(OAc)2/PA-Ph 1 catalyst system facili-
tated Suzuki-type couplings of alkyl halides and tosylates contain-
ing b-hydrogens with either boronic acids or alkylboranes.6e The
activities for the Pd–PA-Ph system rival some of the more common
mono- and bidentate phosphine ligands which have been success-
fully used in palladium-catalyzed formation of C–N, C–O, and C–C
bonds.9 In this Letter, we report on the extension of these studies
using the palladium–PA-Ph system to carbonylative cross-coupling
OH
O
O
N
H
O
OH
O
OH
Platensimycin 4
In conjunction with our work on the synthesis of bioactive com-
pounds,10 we became interested in the potent antibiotic platensi-
mycin 4, recently discovered by researchers at Merck,11 as a
viable candidate for the application of our carbonylation methodol-
ogy. Platensimycin contains a tetracyclic enone unit attached via
amide linkage to an aminoresorcylic acid core. The structure repre-
sents a new class of antibiotic isolated from cultures of Streptomyces
platensis exhibiting potent, broad-spectrum Gram-positive antibac-
terial activity manifested via selective inhibition of cellular lipid
biosynthesis.11 In view of its mode of action, platensimycin shows
no cross-resistance to other key antibiotic-resistant strains, making
* Corresponding author. Tel.: +1 905 525 9140x27393; fax: +1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.105

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J. McNulty et al. / Tetrahedron Letters 50 (2009) 4087–4091
tem comprising 3% Pd(OAc)2, 3% PA-Ph, 1.5 equiv Cs2CO3, 2 equiv
O
Nu
X
methanol, CO (45 psi), and DMF (at 80 °C) was readily identified
using 4-iodotoluene as substrate. This initial screen provided butyl
(4-methyl)benzoate in 97% isolated yield, after only 6–7 h. With
these standard conditions in hand, the scope of the reaction was
then rapidly expanded to include a selected series of aryl and vinyl
substrates in reaction with a range of nucleophiles (Table 1). With
methanol as nucleophile, aryl iodides and bromides, para-substi-
tuted with either electron-releasing or electron-withdrawing
groups gave the corresponding methyl esters in excellent yields
(Table 1, entries 1, 2, 5 and 6). Aryl chlorides and triflates suffered
from poor conversion to the ester products (Table 1, entries 3 and
4). We and others have made similar observations for these
substrates.6g,7f,13 However, some success has been achieved with
carbonylation of aryl chlorides using palladium complexes of 1,
4-bis(diphenylphosphino)- butane(dppb), 1,4-bis(diphenylphos-
phino)ferrocene (dppf), and 1,4-bis(dicyclohexylphosphino)ferro-
cene (dcpf),14 as well as employing more electrophilically
activated substrates (such as 4-chloroacetophenone) in conjunc-
tion with alcohols of low nucleophilicity, such as 2,2,2-trifluoro-
ethanol.13 As far as ortho-steric effects are concerned, these were
Pd(OAc)2, PA-Ph, Cs2CO3, CO (45 psi),
Nucleophile, DMF, 80 oC, 6-7 hr
R
R
X = I, Br, Cl, OTf
Nu = OH, OR', NR'2
Scheme 1. Carbonylation with Pd(OAc)2/PA-Ph catalyst system.
it a highly privileged lead for drug design and biological evalua-
tion.12 Herein we detail our findings that palladium complexes of
1 are useful general catalysts for the hydroxy-, alkoxy-, and amino-
carbonylation of aryl and vinyl halides. In addition, we describe a
novel approach toward the synthesis of the aromatic core of platen-
simycin 4. This route installs the carboxylic group using Pd(OAc)2/
PA-Ph-catalyzed methoxycarbonylation of a nitroresorcinol halide,
leading to functionalized sulfonamide analogs.
The general reaction for carbonylation with the Pd(OAc)2/PA-Ph
catalyst system is outlined in Scheme 1. An efficient catalyst sys-
Table 1
PA-Ph-mediated carbonylative cross-coupling
3% Pd(OAc)2, 3% PA-Ph, Cs2CO3
CO (45 psi), Nu, DMF, 80 oC, 6-7 hr
R-X
R-CO-Nu
A
B
Entry
1
R–X
Nu
Product B
Isolated yield of B (%)
97
CO2Me
CO2Me
CO2Me
I
MeOH
Br
Cl
2
3
MeOH
MeOH
85
30
CO2Me
OTf
4
5
MeOH
MeOH
22
98
CO2Me
I
O2N
O2N
O2N
O2N
CO2Me
Br
6
7
8
9
MeOH
MeOH
MeOH
i-PrOH
94
81
83
70
CO2Me
NO2
Br
NO2
CO2Me
Br
(E)/(Z)=90/10
Br
(E)/(Z)>99
CO2iPr
O2N
O2N

J. McNulty et al. / Tetrahedron Letters 50 (2009) 4087–4091
4089
Table 1 (continued)
Entry
R–X
Nu
Product B
Isolated yield of B (%)
66
Br
CO2iPr
NO2
10
11
12
13
14
15
16
17
18
19
20
i-PrOH
NO2
CO2iPr
Br
i-PrOH
t-BuOH
t-BuOH
t-BuOH
H2O
67
40
38
35
74
86
77
75
83
84
(E)/(Z)=90/10
Br
(E)/(Z)>99
CO2tBut
O2N
O2N
Br
CO2tBut
NO2
NO2
CO2tBut
Br
(E)/(Z)=90/10
(E)/(Z)>99
CO2H
Br
CO2H
Br
H2O
O2N
O2N
Br
CO2H
NO2
H2O
NO2
CO2H
Br
H2O
(E)/(Z)=90/10
(E)/(Z)>99/1
CONEt2
Br
NHEt2
NHEt2
CONEt2
Br
O2N
O2N
seen to be minimal (Table 1, entry 7), while vinyl substrates (e.g.,
b-bromostyrene) were converted to the corresponding ,b-unsatu-
boxylic acids in 74–86% isolated yield. Electronic and steric effects
again appear to be minimal (entries 15–18). The use of a secondary
amine as incoming nucleophile was also demonstrated in the con-
version of aryl bromide substrates to the corresponding diethyla-
mides (Table 1, entries 19 and 20).
Returning to platensimycin 4, we were interested in the synthe-
sis of structural mimics incorporating the natural aromatic core
but replacing the bulky tetracyclic enone residue with a lipophilic
a
rated ester (Table 1, entry 8) with complete (E)-geometry in 83%
isolated yield. A pronounced steric effect of the nucleophile was
observed in going from methanol to i-PrOH to t-BuOH which
caused a decrease in yield as the bulk of the alcohol increased
(e.g., compare Table 1, entries 6, 9, and 12). Hydroxycarbonylation
was easily facilitated with both aryl and vinyl halides giving car-

4090
J. McNulty et al. / Tetrahedron Letters 50 (2009) 4087–4091
sulfonamide moiety. Sulfonamides represent a classic component
of antibiotics,15 and related FAB inhibitors incorporating aryl sul-
fonamide residues have also been recently reported.15b This func-
tional group provides hydrolytic stability under both chemical
and biological conditions. Our overall approach to the synthesis
of these derivatives is outlined in Scheme 2.
The base-catalyzed double methylation of commercially avail-
able 2-nitroresorcinol 5 with dimethylsulfate (DMS) gave nitrodi-
methylether 6 in near quantitative yield. This was smoothly
iodinated at room temperature with I2/Ag2SO4 (1:1) in methanol
to nitroaryl iodide 7 (97% yield) (Scheme 2). With this intermediate
in hand, Pd(OAc)2/PA-Ph catalyzed methoxycarbonylation was
successfully carried out under the conditions outlined in Table 1,
affording the desired nitroester 8 in 95% isolated yield. 17 We note
that the use of several other mono- and bidentate ligands were at-
tempted in this specific alkoxycarbonylation including triphenyl-
To date, four different approaches toward the synthesis of the
aminoresorcylic acid core of platensimycin have been pub-
lished.12a,16 Nicolaou et al.12a utilized a directed ortho-metalation
(DOM) strategy on the bis-MOM-Boc-protected aminoresorcinol
followed by quenching with methyl cyanoformate to install the
carboxylate group (in 45% yield over the last two steps in a five-
step sequence). In the second procedure,16a direct nitration of com-
mercial methyl 2,4-dihydroxybenzoate afforded a (1:1) mixture of
3- and 5-nitro-2,4-dihydroxybenzoates (in 68% isolated yield)
which were separated by fractional crystallization and elaborated
further to the bis-MOM functionalized aniline. In the third ap-
proach,16b a Kolbe–Schmitt electrophilic aromatic carboxylation
placed the carboxyl group ortho to the phenol in several 2-ami-
doresorcinol substrates, in 15–52% yield. In the most recent ap-
proach, the carboxyl group was efficiently introduced (78% yield)
to a bis-MOM-protected 2-nitroresorcinol iodide via metal-halo-
gen exchange with PhMgBr and subsequent quenching with
methyl cyanoformate.16c It is clear from these reports that the pal-
ladium-catalyzed carbonylation described herein offers a more
concise and efficient route to the aminoresorcylic acid core of
platensimycin.
In summary, we have shown that palladium complexes of PA-
Ph 1 are highly effective catalysts in the carbonylation of aryl as
well as vinyl halide substrates, with the scope of the reaction being
limited by aryl chlorides. Application of the Pd(OAc)2/PA-Ph cata-
lyst system to the carbonylation of a functionalized nitroresorcinol
iodide allowed for the regioselective introduction of the carboxyl
group, leading to the platensimycin aminoresorcylic acid core
which was elaborated further to novel sulfonamide analogs. Bio-
logical evaluation of these and other targets of interest are pres-
ently being actively pursued.
phosphine,
tri-tert-butylphosphine,
tricyclohexylphosphine,
phosphorinane 2, dtbpx 3, dppb, dppf and dcpf. All of these led only
to poor conversions to ester product (7 to 8). Furthermore, the
bromide corresponding to 7 was unreactive under a variety of
conditions utilizing the ligands described above, and provided up
to ꢀ50% conversion to 8 using the Pd(OAc)2/PA-Ph system. Thus
the critical alkoxycarbonylation of 7 to 8 required both the use of
the aryl iodide derivative 7 as well as the reactive Pd–PA-Ph
catalyst system for efficient turnover. Catalytic reduction of 8
proceeded without event to give amino ester 9 which was subse-
quently converted to the corresponding sulfonamide ester 10–12,
respectively, in 93–96% yield. Demethylation of both methyl ethers
and the methyl ester was achieved in one pot using boron
tribromide (3.5 equiv) in chloroform, furnishing the respective
sulfonamide acids 13–15 in good overall yields.
NO2
NO2
NO2
HO
OH
MeO
OMe
MeO
OMe
I
DMS, K2CO3, ACN,
I2, Ag2SO4, MeOH,
reflux, 5 hr
98%
rt, 8 hr
97%
7
6
5
Pd(OAc)2, PA-Ph, CO (45 psi),
MeOH, Cs2CO3, DMF, 80 oC, 6-7 hr
95%
R
O
S
O
NH2
NO2
Cl
R
MeO
OMe
OMe
MeO
OMe
H2, Pd/C, MeOH,
O
S
O
TEA, THF, rt,
3 hr
93-96%
60 oC, 6 hr
96%
NH
OMe
MeO
OMe
9
8
O
O
OMe
10-12
O
BBr3, CHCl3, rt, 7 hr
80-85%
Me
R
13. R =
14. R =
O
S
O
NH
HO
OH
O
O
OH
15. R =
O
Scheme 2. Methoxycarbonylation as key-step in synthesis of platensimycin sulfonamide analogues.

J. McNulty et al. / Tetrahedron Letters 50 (2009) 4087–4091
4091
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Acknowledgements
We thank NSERC, Cytec Canada Inc. and McMaster University
for financial support of this work.
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17. Synthesis of methyl (2,4-dimethoxy-3-nitro)benzoate 8. 2,4-Dimethoxy-3-nitro-
1-iodobenzene
7 (0.300 g, 0.971 mmol), palladium(II) acetate (6.5 mg,
0.0291 mmol), and PA-Ph (8.5 mg, 0.0291 mmol) were added consecutively
to a steel reactor in a glove box under nitrogen, followed by 2 ml dry DMF
(2 ml/mmol), methanol (80
ll, 1.94 mmol), and Cs2CO3 (0.474 g, 1.46 mmol).
The reactor was sealed and connected via Swage line to a cylinder of CO. After
three purges, the reactor was pressurised to 45 psi, submerged in an oil bath
set at 80 °C and stirred via an internal magnet. After ꢀ7 h, TLC (30% EtOAc/Hex)
indicated the reaction to be complete. The mixture was diluted with saturated
NH4Cl, extracted with ethyl acetate (3 Â 5 ml), the combined organic fractions
dried (Na2SO4), filtered, and concentrated to an amorphous residue which was
chromatographed (30% EtOAc/Hex) on silica to give methyl (2,4-dimethoxy-3-
nitro)benzoate 8 (95%). 1H NMR (CDCl3, 200 MHz); d (ppm): 8.02 (1H, d,
J = 9.0 Hz), 6.81 (1H, d, J = 9.0 Hz), 3.96 (3H, s), 3.94 (3H, s), 3.91 (3H, s). 13C
NMR (CDCl3, 50 MHz); d (ppm): 164.8, 157.3, 154.9, 134.6, 117.3, 107.4, 106.9,
64.5, 56.9, 52.6.